Research News

Jenny Morton, a professor of neurobiology at Cambridge University, with transgenic sheep imported from New Zealand to assist with research into Huntington’s disease. Photograph: Antonio Olmos for the Observer

"It is hoped to gain a more detailed picture from these tests of how cognitive decline progresses and so pave the way for drugs to slow its impact," says longtime Huntington's disease researcher Jenny Morton.

My father was a folk song collector, and I grew up listening to the music of Woody Guthrie. On July 14th, folk music enthusiasts will be celebrating the 105th anniversary of Guthrie’s birth in his hometown of Okemah, OK. Besides being renowned for writing “This Land is Your Land” and other folk classics, Guthrie has another more tragic claim to fame: he provided the world with a glimpse at the devastation caused by a rare, inherited neurological disorder called Huntington’s disease.

When Guthrie died from complications of Huntington’s a half-century ago , the disease was untreatable. Sadly, it still is. But years of basic science advances, combined with the promise of innovative gene editing systems such as CRISPR/Cas9, are providing renewed hope that we will someday be able to treat or even cure Huntington’s disease, along with many other inherited disorders.

My own lab was part of a collaboration of seven groups that identified the Huntington’s disease gene back in 1993. Huntington’s disease occurs when a person inherits from one parent a mutant copy of the huntingtin (HTT) gene that contains extra repetitions, or a “stutter,” of three letters (CAG) in DNA’s four-letter code. This stutter leads to production of a misfolded protein that is toxic to the brain’s neurons, triggering a degenerative process that, over time, leads to mood swings, slurred speech, uncontrolled movements, and, eventually, death. In a new study involving a mouse model of Huntington’s disease, researchers were able to stop the production of the abnormal protein by using CRISPR tools to cut the stutter out of the mutant gene.

The progress, reported in the Journal of Clinical Investigation [1], comes from the NIH-supported team of Su Yang, Renbao Chang, Xiao-Jiang Li, and colleagues at Emory University School of Medicine, Atlanta. The group’s previous work showed that halting the production of mutated (or even healthy!) HTT protein in mature neurons doesn’t hurt the cells or cause obvious neurological problems in mice [2]. So, the researchers now wanted to see if halting HTT production in millions of neurons in the striatum, which is a part of the inner brain that controls motor skills, could reverse early signs of disease that typically appear in affected mice before the age of 9 months.

To get their answers, the researchers injected millions of inactivated viral particles directly into the striatum of a few 9-month-old mice, engineered to produce the mutant form of HTT protein. Each particle, like a Trojan horse, delivered to the neurons one of the two pieces of the CRISPR/Cas9 editing system: either a short guide RNA sequence to mark for removal the HTTgene’s CAG repeats or a scissor-like Cas9 enzyme to snip out the repeats. In this strategy, both the health and abnormal copies of the HTT gene were “knocked out,” resulting in the production of no HTT protein.

Remarkably, three weeks later, the researchers found that the CRISPR/Cas9 gene editing had reversed the disease process in their mouse model. Neurons in the striatum had stopped making the HTT protein. What’s more, the toxic, abnormal HTT protein that had already clumped together in and around the neurons—and which likely would have would have killed them—had begun to clear to varying degrees in the mice. The same went for other protein abnormalities associated with the progression of Huntington’s disease.

There was even better news to come. The Emory team repeated the CRISPR/Cas9 injections into the striatum of a dozen 9-month-old mice and got a similar protein-clearing outcome. Then, over the next three months, the researchers found that the animals’ balance, muscle coordination, and mobility had improved compared to mice given sham shots of CRISPR/Cas9. Interestingly, the degree of improvement in their motor skills corresponded with the amount of toxic protein that had been cleared from the striatum.

As exciting as gene editing is as a potential treatment for Huntington’s disease, the research is still very much in its early stages. For example, while the Emory researchers were able to establish that adult mice could live well without a functioning copy of HTT, they remain uncertain whether that’s also the case in humans.

Another potential safety concern with CRISPR/Cas9 is off-target editing. Last May, in a very controversial article, it was reported that CRISPR/Cas9 can sometimes go astray and snip away at healthy genes in animal studies, leaving behind hundreds of unintended mutations in its wake [3]. However, the Emory team reported that off-target editing did not appear to be a major problem in its latest study. Sequencing of genomic DNA taken from the striatum of the mice showed that CRISPR/Cas9 editing occurred “predominantly” around their target sequences without significant genomic editing in the most likely off-target locations. While this is only one study, it’s reassuring news as more animal studies testing the potential curative power of CRISPR/Cas9 editing move forward.

This utilization of CRISPR/Cas9 to pursue a cure for Huntington’s disease is one more example of how this powerful new technology might be applied to the thousands of diseases due to a specific mutation in DNA; efforts are already underway for other conditions like sickle cell disease and muscular dystrophy. Given the promise, the NIH Common Fund is actively exploring ways in which this approach could be accelerated.

To the families in the front row from Venezuela – Barranquitas and San Luis, he kissed and consoled a crying mother weeping that she was living in a tin shack surrounded by garbage and barbed wire, without food or water. She has HD and her family has abandoned her. The Pope consoled her in Spanish and the relief was palpable on her face. Next he consoled and hugged Anyervi, a 13 year old with juvenile HD who had been shunned and banned from school because people mistakenly believe HD is infectious.

Charles Sabine, one of the organizers of the Hidden No More event, made the wishes of several of the children come true! Anyervi, before meeting the Pope, was presented with a soccer ball and Champion’s League shirt by his soccer hero.

Children from HD families in Venezuela have no toys – only garbage bags, plastic bottles or other trash they may creatively turn into something.

Then came Brenda, a 15 year old girl with juvenile HD from Argentina. The Latin superstar Axel serenaded her with her favorite song. Before our enthusiastic eyes, her wishes came true!

All the families had a joy, wonder and relaxation that they have never before known! They became children again!

The families from Colombia and Argentina were next. With each, the Pope stopped thoughtfully and listened. He paid attention to each person. To the woman with HD in a wheel chair from Puerto Rico, he bent down to kiss her. To the man from Ireland with HD who kept jumping up to greet him, he offered his hand to help him sit down. He blessed rosaries and pictures of relatives lost to HD and permitted “selfies” with awestruck family members.

When I greeted him, I told him that I discovered the HD gene. I told him I am at risk for HD since my mother died of it. I told him finding the HD gene was entirely thanks to the Venezuelan families. I told him I loved the Venezuelan families sitting in the front row. I told him I had taken care of them and their family members. I thanked him for supporting research in his speech! I promised him we would find the cure and bring it to Venezuela for free!

He hugged me back and was so warm, gracious, kind and focused on me. I knew I was in the presence of a kind of beatitude and warmth that radiates from him!

He personally greeted, listened to and consoled more than 150people. He spent more than one hour with us - we never felt he was rushed.

He began his Audience with a speech which has many pearls of wisdom in it. He began with an admonition. He said of Hidden No More: “It is not simply a slogan, so much as a commitment that we all must foster.” It must become so much more. It must become the launching pad for dignity and not returning to the shadows of shame and humiliation.

Huntington's disease is a brain disease, not a sin or a crime. The Pope spoke about Jesus: “Throughout [Jesus’s] ministry, He met many sick people; He took on their suffering; He tore down the walls of stigma and of marginalization that prevented so many of them from feeling respected and loved. For Jesus, disease is never an obstacle to encountering people, but rather, the contrary. He taught us that the human person is always precious, always endowed with a dignity that nothing and no one can erase, not even disease. Fragility is not an ill. And disease, which is an expression of fragility, cannot and must not make us forget that in the eyes of God our value is always priceless.”

Next he turned to the families: “Those who experience Huntington’s disease know that no one can really overcome loneliness and despair if they do not have people at their side who, with self-sacrifice and steadfastness, make themselves ‘travel companions.’ You are all this: fathers, mothers, husbands, wives, children, brothers and sisters who, on a daily basis, silently but effectively, accompany your family members on this difficult path.”

He talked about the importance of family members and others who are good at taking care. He talked about the value of good, thoughtful caring.

He advocated for increased research on the brain and genes. He recognized that there are no treatments or cures for HD. He talked about the need for better diagnoses and handling the delicate and precarious state of first diagnoses. He spoke to the need for attention to the living circumstances of patients and families.

Above all, he advocated for the dignity of the sick, poor, hungry and humble. Everyone – including me – cried meeting a man so accepting. Because the symptoms of HD can be very physically and psychologically alienating, many people fail to take the time to know patients and families.

HD affects every aspect of movement, mood and memory. The uncontrollable movements in all parts of your body fling you around like you are under the strings of a puppeteer. Movements may make you shred clothing and bedclothes. Hallucinations and paranoid delusions in someone with HD may make it impossible for someone else to give them food, drink or medicines. They fear they are being poisoned. Cognitive problems make it hard to learn new things. Choking is a constant hazard and people are starving. The suicide rate is high. These all are part of the illness itself.

Patients and families are often shunned. The fact that there are no effective treatments and cures makes their situation even more perilous.

My sister and I were taught not to mention having HD in our family because we could lose jobs and insurance. We were advised we should not have children.

Obituaries of friends who suffered from HD often hide the cause of death for fear that the rest of the family will be stigmatized and ostracized, knowing that HD is hereditary.

The Pope teaches us to be brave and stick up for dignity and grace. Having so many people in the room who share a genetic risk and fate gives us courage to take the next steps out of darkness and stigma and shame to create a better life for all of us!

In all, people representing 23 countries attended and many more around the world heard his important message.

Having almost 2,000 people assemble to heed the Pope’s message, in the world’s largest convocation yet of patients, families and researchers, I am even more moved and motivated by the enormous momentum to change the world for the better!!

HDF President Nancy Wexler is honored to join HD families for papal audience TOMORROW, May 18. Learn more about this important and historic event - and watch it live at the below links starting at 11:30 am (Rome) on Thursday:

New York – The Hereditary Disease Foundation will be participating in an historic meeting of Pope Francis with individuals and families with Huntington’s disease on Thursday, May 18, 2017 at the Vatican. This special audience with Pope Francis brings international attention to the tremendous suffering of people affected by Huntington’s disease throughout the world and particularly in South America.

Attending this landmark meeting is Nancy Wexler, PhD, President of the Hereditary Disease Foundation, an organization dedicated to finding treatments and cures for Huntington’s disease and other brain disorders.

Dr. Wexler says, “Even today, men, women and children with Huntington’s disease in South America and around the world are hiding in the shadows. This audience with Pope Francis will shine a bright light on Huntington’s disease and help dispel the stigma and fear that multiplies the suffering of patients and families. We are honored to participate and deeply grateful to Pope Francis and the Vatican.”

Huntington’s is a hereditary disease causing an irreversible decline in control over movement, mood, and memory. It is caused by a single dominant gene. Each child of a parent with Huntington’s has a 50% risk of inheriting the same lethal gene. There is no cure and it is fatal over a 10 to 20 year period. Huntington’s usually strikes between the ages of 30 and 40, though children as young as two and adults in their eighties may develop symptoms. People in the late stages of the illness require enormous assistance. They lose the ability to walk, talk, and feed themselves, but are still often conscious, aware and know themselves and their families.

Among special invitees to the historic visit with Pope Francis are Sir Michael Rawlins, FMedSci, MD, a distinguished Huntington’s researcher, advocate and supporter of the Hereditary Disease Foundation. Also invited is Margot de Young, MD, who together with the Hereditary Disease Foundation, created and has directed a clinic and nursing home in Maracaibo, Venezuela for Huntington’s patients.

The Vatican meeting is organized under the auspices of HDdennomore, a global coalition of patient advocates dedicated to raising awareness of Huntington’s disease and ending the stigma and shame that surround the disease. www.HDdennomore.com

The Hereditary Disease Foundation and the Venezuelan HD Families

Since 1968, the Hereditary Disease Foundation’s mission is to discover and fund innovative, catalytic research towards curing Huntington’s disease and impacting other brain disorders. Beginning in 1979, Dr. Wexler has led the international team of researchers working with Venezuelan Huntington’s disease families. Venezuela has the world’s highest prevalence of Huntington’s disease. Dr. Wexler and her team have assembled a family tree encompassing more than 18,000 individuals over 10 generations. With the extraordinary collaboration of the Venezuelan families, the Hereditary Disease Foundation has made crucial medical and scientific discoveries. The Venezuelans’ critical contribution allowed the Hereditary Disease Foundation, in 1983, to find the first DNA marker for any genetic disease. A decade later, the Hereditary Disease Foundation discovered the HD gene itself. The Hereditary Disease Foundation’s discoveries launched the Human Genome Project. The Foundation proudly acknowledges and thanks the Venezuelan families publicly for all they have helped to accomplish. They have actually changed the face of medicine today. Dr. Wexler continues her work as a passionate scientist and advocate for treatments and cures for Huntington’s disease. www.hdfoundation.org

Live English Broadcast of Historic Huntington’s Community Papal Audience on

The Hereditary Disease Foundation is proud to kick off HD Awareness Month by partnering with Lundbeck, a global pharmaceutical company dedicated to helping people who are living with brain disorders, on the 8th annual Build Hope for HD campaign.

The Build Hope campaign generates support for the Casa Hogar Amor y Fe (House of Love and Hope), a Venezuelan clinic serving the families who made possible groundbreaking discoveries for the treatment of Huntington’s disease (HD) and other genetic diseases.

Visit BuildHopeforHD.com to learn how you can trigger a donation from Lundbeck to the Casa Hogar. For each LIKE, COMMENT and SHARE on Build Hope for HD posts, Lundbeck will donate $15, up to $25,000. Since 2010, the Build Hope for HD campaign has raised more than $335,000. Lundbeck has pledged to support the campaign through 2019.

Lundbeck has supported important research through its HD Research Initiative, and participated in hundreds of local HD events nationwide – from disease awareness walks to education seminars, and more. Partnering with the HD community has fueled their passion to make a difference…one patient at a time.

For years, Xenazine (tetrabenazine) was the only drug approved by the FDA to treat the chorea associated with Huntington's disease. Now HD families have TWO FDA-approved drugs to treat chorea! Austedo sticks around longer in the body which means it’s potentially easier to dose.It’s very valuable to have options!

The Huntington Study Group did a clinical trial comparing Austedo with Xenazine head-to-head and against placebo as well. Austedo did very well in controlling the chorea. The findings from the Huntington Study Group study led directly to the FDA approving it. As it is FDA-approved, it may be covered by insurance.

The Hereditary Disease Foundation (HDF) is honored to take part in the historic meeting of Huntington's disease families with Pope Francis at the Vatican in Rome on May 18, 2017. This landmark event brings international attention to the tremendous suffering of HD patients and families throughout the world and particularly South America.

The global HD community coming together with Pope Francis will help dispel the stigma and fear that multiply the suffering of patients and families with HD. By mobilizing action to improve the lives of HD families, we offer hope and sustenance for the future.

Even today, worldwide, men, women and children with HD are still hiding in the shadows. Huntington’s disease is a family disease affecting those with the disease and all other family members.

Families often feel shame and embarrassment about the illness. Its unique combination of symptoms affecting movement, mood and memory attacks our humanity so patients and families face tremendous challenges. In many cases, patients and their families are forced to live on the fringes of society due to fear and misunderstanding.

Nancy Wexler, Ph.D., President of the Hereditary Disease Foundation, will be attending this historic meeting with Pope Francis. Since 1979, she has led the international team working with Venezuelan Huntington's disease families. Venezuela has the world’s highest prevalence of Huntington's disease. Dr. Wexler has assembled a family tree encompassing more than 18,000 individuals over 10 generations. With the extraordinary collaboration of the Venezuelan families, the Hereditary Disease Foundation has made crucial medical and scientific discoveries. The Venezuelans’ critical contribution allowed the Hereditary Disease Foundation, in 1983, to find the first DNA marker for any genetic disease. A decade later the Hereditary Disease Foundation discovered the HD gene itself. The HDF’s discoveries launched the Human Genome Project. The Hereditary Disease Foundation acknowledges the Venezuelan families publicly for all they have helped to accomplish. They changed the face of medicine today. Dr. Wexler continues her work as a passionate scientist and advocate for treatments and cures for HD.

Margot De Young, M.D., who, with the support of the Hereditary Disease Foundation, created and directs the Casa Hogar de Amor y Fe, a clinic and nursing home in Maracaibo, Venezuela, has also been invited. The Casa Hogar provides integrated and unique medical care for treating people with Huntington's with love, dignity and respect. Sir Michael Rawlins, M.D., an active HD researcher and advocate, will attend as well.

We are grateful to Charles Sabine, of London, former NBC war correspondent and television journalist; neuroscientist Ignacio Munoz-Sanjuan, Ph.D.; and Elena Cattaneo, Ph.D., distinguished Huntington's researcher in Milano and Lifetime Senator in the Italian Parliament, for organizing this event.

Details for this historic meeting between the Huntington's disease community and Pope Francis are being finalized. Please check www.HDdennomore.com for further developments.

We are deeply saddened to say goodbye to our mentor, longtime colleague and beloved friend P. Michael Conneally (Mike), who died on February 17, 2017 at the age of 85.

Mike was a Professor of Genetics at the Indiana University School of Medicine who played a crucial role in almost every aspect of Huntington's disease research starting in the late 1960s. He was one of the investigators who helped make the breakthrough discovery of the genetic marker for Huntington's in 1983. He also participated in the landmark collaborative group that mapped the actual HD gene in 1993. But there was much more.

As a geneticist, Mike early on appreciated the importance of linkage for mapping genes and spent years using traditional genetic markers in an effort to find linkage with the HD gene. When the new DNA markers became available in the late 1970s, he immediately understood their value. He encouraged the HDF to support the search for the gene using these markers at a time when many scientists thought this was premature. He also understood the value of large families for mapping genes. In the 1970s he had begun collecting samples and building pedigrees of HD families in the American midwest. These became the basis of the Huntington's Disease Research Roster at Indiana University which Mike helped establish and which the Hereditary Disease Foundation continues to support. The Roster remains an invaluable resource for investigators.

Mike served on the historic Congressional Commission on Huntington's Disease in the 1970s as a member of the Venezuela Working Group. After Nancy Wexler started the annual research trips to Venezuela in 1981, Mike came along on many of these expeditions, helping with the pedigree of families and entertaining the kids. He also served for many years on the Scientific Advisory Board of the HDF, enlivening many Foundation parties with his wonderful Irish sense of humor, his generosity and his love of life. Mike's legacy lives on in the many generations of students he trained. But the inimitable Mike Conneally in person will be deeply missed.

A 20% cut - $6 billion - in the NIH budget will have devastating effects on the development of effective therapies for terrible fatal diseases. This cut will mean that only 2-5% of approved grants will be funded. Young scientists will be disproportionately affected, essentially guaranteeing a loss of at LEAST one generation of scientists. Philanthropic support is even more critical now with this dire situation in Washington, D.C.

Please PHONE or write your senators and representatives to urge an INCREASE, not a DECREASE, in the NIH budget. Phone calls can make a difference! Even one phone call can help!

For phone numbers online go to www.senate.gov and click on "Find Your Senators"; for representatives go to www.house.gov and click on "Find Your Representative".

Pi-O-Neering gene hunter and trailblazer of the Human Genome Project Nancy Wexler is taking a pie in the face for the cure - and challenges you to do the same. We are SO close to the cure that will help us SOLVE BRAIN DISEASE but we need YOUR help. Join us and spread the word! No pie in the face, please donate to the Hereditary Disease Foundation #cures, @hdfcures

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